1. Field of the Invention
The invention relates generally to oncolytic virus for cancer treatment and more specifically to the use of RNA interference mechanism in a modified oncolytic adenovirus for treatment of cancers including prostate cancer.
2. Background Information
Despite escalating research efforts for treatment of prostate cancer, advanced prostate cancer (PCa) remains incurable. Traditional chemotherapeutic strategies do provide some benefits by nominally extending life expectancy (less than 2.5 months) for hormone resistant disease, yet resistance to such therapies remains a serious clinical problem. One strategy for approaching this recalcitrant disease has been the development of prostate-specific conditionally replicating adenoviruses (CRAds). Prostate-specific CRAds are generated by placing the adenoviral genes responsible for controlling replication (E1A, E1B, or E4) under the control of a prostate-specific promoter. Early prostate-specific CRAds utilized the PSA promoter and enhancer to control E1A expression or the rat probasin promoter to control E1A plus the PSA promoter and enhancer to control E1B. Although this strategy has shown clinical efficacy in early phase trials, the potency of these viruses has been inadequate to be considered for a single modality therapy.
Adenoviruses infect both quiescent and non quiescent cells and are known to replicate their genome inside the host cell nucleus. However, once inside the host cell the virus needs to overcome multiple challenges before it can propagate its progeny. Besides tumor suppressors like p53 and Rb, cell cycle regulation is one of the hindrances that the virus encounters. Adenoviruses have evolved multiple methods that help overcome these barriers. It is now believed that the immediate adenovirus early gene, E1A, regulates the expression of host and viral genes and creates a cellular environment favorable for viral replication. Based on the importance of E1A in adenoviral biology, the majority of adeno-gene therapy vectors rely on either replacing E1A gene from the virus backbone with the gene of interest or using tissue/cancer specific promoters to limit viral replication to specific tissues and organs. Although these manipulations helped in restricting viral replication to the tissue of interest, using promoters other than the endogenous viral promoters attenuates its replication potential and therefore compromise viral cytotoxicity.
Therefore, there remains a need for modified and improved oncolytic viruses for the treatment of cancers, in particular prostate cancer.